1. Field of the Invention
The present invention relates to a method of preventing or treating the inflammatory response of an inflammatory bowel disease by administering anti-sense oligonucleotides of the signal transducer and activator of transcription-4 (STAT-4).
2. Background Art
There is growing evidence that Crohn""s disease (CD) and ulcerative colitis (UC), the two major forms of human inflammatory bowel disease (IBD) are due to dysregulated intestinal immune responses to one or more luminal antigens in the normal intestinal microflora (1-4). These responses are characterized by abnormalities of both CD4+ and CD8+ T cells which manifest both as disordered T cell activation and regulatory function and as cytokine production disturbances that lead to inflammation (2, 5-9).
Over the last several years, various murine models of chronic intestinal inflammation resembling IBD have been established which have provided important new insights into the pathogenesis of both CD and UC (10). Thus, in studies of several of the models most closely resembling CD it has been shown that production of large amounts of Th1-type cytokines, e.g., interferon-xcex3 (IFN-xcex3) and tumor necrosis factor-xcex1 (TNF-xcex1), by CD4+ T cells is a major and essential feature of the inflammation (6-7, 11). In addition, it has been demonstrated that this disease-causing Th1 cytokine response can be counteracted by induction of a suppressor response involving the generation of T cells producing Th2-type cytokines (IL-4, IL-10) and/or suppressive cytokines, such as TGF-xcex2 (12-16). Finally, it has been shown that the Th1 cytokine production in these models is triggered by increased production of IL-12, a cytokine that plays a major role in driving T cell differentiation (17). In the latter regard, increased IL-12 production can be detected in the inflamed intestinal tissues of mice with experimental inflammation and, more importantly, systemic administration of anti-IL-12 to such mice leads to abrogation of the inflammation (7, 11). The relevance of these findings to CD is inherent in studies showing that this disease is also associated with an excessive Th1 T cell response characterized by increased IFN-xcex3 production by lamina propria (LP) T cells (9). In addition, a recent report indicates that CD LP cells produce small, but measurable increases, in IL-12 in response to LPS (18).
Interleukin-12 (IL-12) is a structurally unique cytokine with several important effects on immune function (17, 19-20). It consists of two disulfide-linked subunits, p40 and p35, which form functionally active p40/p35 heterodimers or, alternatively, inactive p40 homodimers which inhibit the activity of the heterodimers in some systems (17). IL-12 is produced mainly by macrophages/monocytes and to a lesser extent by B cells and follicular dendritic cells. It mediates its biological effects by binding to a receptor comprised of a xcex21 chain and a xcex22 chain which are differentially expressed in Th1 and Th2 T cells (21-25): while the xcex21 chain is expressed in both cell types, the xcex22 chain is expressed only in Th1 cells. Thus, it is the expression of the xcex22 chain that accounts for the responsiveness of Th1 cells and the non-responsiveness of Th2 cells to IL-12 (24-25). After IL-12 binds to its receptor, it induces activation of specific members of the STAT (Signal Transducers and Activators of Transcription) family of transcription factors (STAT-3 and STAT-4), which then translocate to the nucleus and bind to genomic promoter regions, including that governing IFN-xcex3 (26-28). STAT-4 is particularly important in this respect, as shown by the fact that STAT-4-deficient T cells manifest impaired production of IFN-xcex3 upon stimulation with antigen (29). In addition, the phenotype of the IL-12-deficient mouse (30) is similar, if not identical, to that of the STAT-4-deficient mouse (29).
The present invention provides STAT-4 anti-sense oligonucleotides which are effective in the treatment and prevention of the inflammatory response of an IBD.
The present invention provides a method of treating or preventing the inflammatory response of an inflammatory bowel disease in a subject, comprising administering to the subject an amount of a STAT-4 antisense oligonucleotide effective in treating or preventing the inflammatory response of the inflammatory bowel disease.
The present invention may be understood more readily by reference to the following detailed description of specific embodiments and the Examples included herein.